Synthesis of Some New Thieno[2,3 b]pyridines, Pyrimidino[4'''',5'''' 4,5]thieno[2,3 b]pyridine and Pyridines Incorporating 5 Bromobenzofuran 2 yl Moiety Molecules 2015, 20, 822 838; doi 10 3390/molecules200[.]
Trang 1molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Some New Thieno[2,3-b]pyridines,
Pyrimidino[4',5':4,5]thieno[2,3-b]pyridine and Pyridines
Incorporating 5-Bromobenzofuran-2-yl Moiety
Nadia Abdelhamed Abdelriheem 1 , Sayed Abdel-Kader Ahmad 2 and
Abdou Osman Abdelhamid 1, *
1 Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt;
E-Mail: nadia.abdelhamid5@gmail.com
2 Department of Chemistry, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt;
E-Mail: Abdelhamid45@gmail.com
* Author to whom correspondence should be addressed; E-Mail: Abdelhamid45@gmail.com;
Tel.: +202-3567-6573; Fax: +202-3572-8843
Academic Editor: Derek J McPhee
Received: 6 December 2014 / Accepted: 29 December 2014 / Published: 7 January 2015
Abstract: 2-Sulfanyl-6-(2-thienyl)pyridine-3-carbonitrile,
1-Amino-6-(5-bromo-benzofuran-2-yl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile, thieno[2,3-b]pyridins, pyrimidino[4',5':4,5] thieno[2,3-b]pyridine, quinazoline and carbamate derivatives were synthesized from sodium
3-(5-bromobenzofuran-2-yl)-3-oxoprop-1-en-1-olate with The newly synthesized compounds
were elucidated by elemental analysis, spectral data, and alternative synthesis whenever possible and chemical transportation
Keywords: thieno[2,3-b]pyridines; pyrimidino[4',5':4,5]thieno[2,3-b]pyridine; pyridines;
5-bromobenzofuran; urea; carbamate
1 Introduction
The thieno[2,3-b]pyridine derivatives occupy special place and have attracted considerable attention
because of their broad pharmacological activities, including anticancer [1–9], antiviral [10–13], anti-inflammatory [14–17], antimicrobial [18,19], antidiabetic [20–23], antihypertensive [24–26] and osteogenic [27,28] activities, in addition to treatment of CNS disorders [29–31] Also, pyridine
Trang 2derivatives of different heterocyclic nucleus have shown potent pharmacological properties like
antifungal [32,33], antitubercular [34], antibacterial [35], antimicrobial [36], insecticida [37] In view of
these findings and in continuation to our previous work [38–43], we report here the convenient synthesis
of Some New thieno[2,3-b]pyridines, pyrimidino[4',5':4,5]thieno[2,3-b]pyridines and pyridines
incorporating 5-bromobenzofuran-2-yl moiety
2 Results and Discussion
Treatment of sodium 3-(5-bromobenzofuran-2-yl)-3-oxoprop-1-en-1-olate (1) [44] with each of
cyanothioacetamide or 2-cyanoacetohydrazide in piperidinium acetate under refluxed to give
6-(5-bromobenzofuran-2-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (2) and 1-amino-6-(5-bromobenzofuran-2-yl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (3), respectively in a good yield (Scheme 1) Structure 2 was elucidated by elemental analysis, spectra, and chemical transformation 6-(5-bromobenzofuran-2-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (2) was reacted with
chloroacetone in N,N-dimethylformamide containing potassium hydroxide to afford the product
corresponding to addition and dehydrochlorination reactions The IR spectrum of this product showed bands at 2218 and 1700 cm−1 corresponding to CN and CO groups Its 1H-NMR spectrum revealed the signals at δ 2.39 (s, 3H, CH3), 4.38 (s, 2H, SCH2) and 7.23–7.97 (m, 6H, ArH’s) Based on these data, these reaction products could be formulated as
2-(2-oxopropylthio)-6-(5-bromobenzofuran-2-yl)pyridine-3-carbonitrile (5a) Further confirmation of the structure of 5a arose from their cyclization in boiling
ethanol containing a catalytic amount of piperidine to give the corresponding
1-(3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridin-2-yl)ethanone (6a) (Scheme 1) The IR spectrum of 6a
showed no band of the CN function but the bands at 3274, 3174 (NH2 group) 1H-NMR spectrum of 6a
revealed an absence of signals of the -SCH2- group and the presence of the NH2 protons These findings proved that the CN and the -SCH2- groups were both involved in the cyclization step leading to 6a
Also, 2 was reacted with each ω-bromoacetophenone and idomethane in N,N-dimethylformamide
containing potassium hydroxide to afford
6-(5-bromo-benzofuran-2-yl)-2-(2-oxo-2-phenyl-ethylsulfanyl)-nicotinonitrile (5b) and 6-(5-bromobenzofuran-2-yl)-2-(methylthio)6-(5-bromo-benzofuran-2-yl)-2-(2-oxo-2-phenyl-ethylsulfanyl)-nicotinonitrile Compound 5b was
converted to (3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridin-2-yl)(phenyl)methanone (6b)
by its boiling in ethanolic piperidine solution 1H-NMR of 6b showed signals at δ 4.05 (s, 2H, NH2), and 7.14–7.78 (m, 11H, ArH’s) (Scheme 1)
In contrast, compound 2 was reacted with each of chloroacetonitrile and ethyl chloroacetate afforded
3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridine-2-carbonitrile (6c) and ethyl 3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridine-2-carboxylate (6d), in a good yield
Structure of 6c was confirmed by elemental analysis, spectral data and chemical transportation Thus, compound 6c was reacted with each of formic acid or formamide to give the corresponding
7-(2-thienyl)-3-hydropyrimidino[4',5':4,5]thieno[2,3-b]pyridine-4-one (7) and 7-(2-thienyl)pyrimidine[4',5':4,5] thieno[2,3-b]pyridine-4-ylamine (8), respectively (Scheme 1) Structures 7 and 8 were established on
the basis of spectral data and elemental analysis Thus, IR spectrum of 7 revealed a band at 1666 (CO)
IR spectrum of 8 revealed bands at 3320, 3151 (NH2) Meanwhile, 6c reacted with triethyl ortho-formate
to give ethyl N-[6-(5-bromo-benzofuran-2-yl)-2-cyano-thieno[2,3-b]pyridin-3-yl]-formimidoate (9)
Trang 3The latter compound was reacted with ammonia or formamide gave a product identical in all aspects
(mp., mixed mp., and spectra) with compound 8
Scheme 1 Synthesis of pyridenes 2, 3, thieno[2,3-b]pyridenes 6a–d and pyrimidine[4',5':4,5]thieno[2,3-b]pyridines 7 and 8
Treatment of 2 with 2,4-pentanedione, ethyl 3-oxobutanoate, ethyl cyanoactate, malononitrile or
benzoylacetonitrile in boiling acetic acid and ammonium acetate under refluxed gave
1-(methylpyridin-3-yl)ethanone (10) and ethyl 6-(5-bromobenzofuran-2-yl)-2-methylpyridine-3-carboxylate (11), ethyl 2-amino-6-(5-bromobenzofuran-2-yl)pyridine-3-carboxylate (12), bromobenzofuran-2-yl)pyridine-3-carbonitrile (13) and 2-amino-6-(5-bromobenzofuran-2-yl)-3-benzoylpyridine (14), respectively (Scheme 2)
Scheme 2 Synthesis of pyridines 10–14
N SH
CN R
R O
N S
CN
NH2 Y
N
NH N O N
N N
NH2 N
N CN CHOC2H5
2
N O
CN R
NH2 ONa
3
7 8
9
R
O
N CH3
CH3
or
R = 5-bromobenzofuran-2-yl
a, X= CH2COCH3
b, X = H 2 COC 6 H 5
c, X = CH3
a, Y = COCH 3
b, Y= COC6H5
c, Y= CN
d, Y = COOC2H5
R = 5-bromobenzofuran-2-yl
R
O
N CH3
CH3
N CH 3
CH3 O
O
R
N CH 3 O O
R
N NH2 O O
R
N NH 2 R
CN
10
11
12
13
14 2
i
iv
v
i = acetylacetone
ii = ethyl acetacetate iii = ethyl cyanoacetate
iv = malononitrile
v = benzoylacetonitrile
Trang 4Next, Compounds 11 was reacted with hydrazine hydrate afforded
2-methyl-6-(2-oxo-2H-chromen-3-yl)pyridine-3-carbohydrazide (15) The structure of 15 was elucidated by elemental analyses, spectra and chemical transformations Thus, compounds 15 was reacted with each of ethyl acetoacetate,
acetylacetone and nitrous acid, gave
2-[6-(5-bromo-benzofuran-2-yl)-2-methyl-pyridine-3-carbonyl]-5-methyl-2,4-dihydropyrazol-3-one (16a),
[6-(5-bromo-benzofuran-2-yl)-2-methyl-pyridin-3-yl]-(3,5-dimethyl-pyrazol-1-yl)-methanone (16b) and 6-(5-bromobenzofuran-2-yl)-2-methylnicotinoyl azide (20), respectively (Scheme 3)
Scheme 3 Synthesis of pyridines 15–18, 20–22, quinazoline 22 and carbamates 23
Structures 16a, 16b and 20 were confirmed by elemental analyses, spectral data and chemical transformations Thus, treatment of 16a and 16b with benzenediazonium chloride in ethanolic sodium acetate gave 17 and 18, respectively Structures 17 and 18 were confirmed by elemental analyses,
spectral data and alternative synthetic route (reaction of the appropriate ethyl
3-oxo-2-(2-phenylhydrazono)butanoate (19a) [45] or 3-(2-phenylhydrazono)pentane-2,4-dione (19b) [46] with 15
in boiling acetic acid under refluxed gave identical product in aspects (mp., mixed mp and spectra) with
corresponding compounds 17 and 18) Structure 20 was established by elemental analyses, spectral and chemical transformation Thus, treatment of 20 with each of the appropriate aromatic amine (aniline,
R = 5-bromobenzofuran-2-yl
N CH3 O O
3
N O
R
NH2
N CH3
N3 O
N
3
CH3
NH O O Ph NH
NH O Ar
N CH3
O
R
N N
CH3
X
N CH3
O
R
N N
CH3
X N
N Ph PhN2Cl
N R
N NH O O
O
H3C X NNHAr
23
16a, b
17, 18
a, X = COCH3
b, X = CO 2 C 2 H 5
20 22
21a-d
i
ii iii
16
iv
v
vi
i = N2H4.H2O
ii = acetylacetone, ethylacetoacetate iii = NaNO2 / HCl
iv = aniline, p-toluidine, p-anisidine, 3-amino -5 -phenylpyrazole
v = anthranilic acid (methyl anthranilate)
vi = phenol, p-nitrophenol, picric acid
19a, b
a, X = OH
b, X = COCH3
17, X = OH
18, X = COCH3
21a, Ar = C6H5
b, Ar = 4-CH 4 C 6 H 4
c, Ar = H3COC6H4
d, Ar = 3(N-imino -5 -phenyl)pyrazolyl
Trang 5p-toluidine, p-anisidine, 3-amino-5-phenylpyrazole or anthranilic acid (or methyl anthranilate) in boiling dioxane and phenol in boiling benzene gave
1-[6-(5-bromo-benzofuran-2-yl)-2-methyl-pyridin-3-yl]-3-substituted urea 21a–d,
3-[6-(5-bromo-benzofuran-2-yl)-2-methylpyridin-3-yl]-1H-quinazoline-2,4-dione (22) and phenyl [6-(5-bromo-benzofuran-2-yl)-2-methyl-pyridin-3-yl]-carbamoate (23) (Scheme 3) Structures 21–23 were elucidated by elemental analyses and spectral data
3 Experimental Section
All melting points were determined on an Electrothermal melting point apparatus and are uncorrected
IR spectra were recorded (KBr discs) on a Shimadzu FT-IR 8201 PC spectrophotometer (Kyoto, Japan)
1H-NMR and 13C-NMR spectra were recorded in CDCl3 and (CD3)2SO solutions on a Varian Gemini
300 MHz (Varian Inc., Palo Alto, CA, USA) and JNM-LA 400 FT-NMR system spectrometer (Japan Electronic Optics Laboratory Co Ltd., Tokyo, Japan) and chemical shifts are expressed in δ units using TMS as internal reference Mass spectra were recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer (70 eV, Shimadzu, Kyoto, Japan) Elemental analyses were carried out at Micro analytical Center of the University of Cairo, Giza, Egypt
3.1 General Procedure for the Synthesis of
6-(5-Bromobenzofuran-2-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (2) and
1-Amino-6-(5-bromobenzofuran-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (3)
Method A: A mixture of sodium 3-(5-bromobenzofuran-2-yl)-3-oxoprop-1-en-1-olate (1) (1.43 g,
5 mmol), the appropriate cyanothioacetamide or 2-cyanoacetohydrazide (5 mmol), and few catalytic drops of acetic acid was thoroughly ground with a pestle in an open mortar at room temperature for 3–5 min until the mixture turned into a melt Grinding of the initial syrup was continued for 5–10 min, and the reaction was monitored by TLC The solid was washed with water and recrystallized from the
appropriate solvent gave the corresponding fused pyridines 2 and 3, respectively
Method B: A mixture of sodium 3-(5-bromobenzofuran-2-yl)-3-oxoprop-1-en-1-olate (1) (1.43 g,
5 mmol) and the appropriate cyanothioacetamide or 2-cyanoacetohydrazide (5 mmol) in a solution of piperidinum acetate (piperidine (2.5 mL), water (5 mL), and acetic acid (2 mL)) was heated under reflux for about 10 min; acetic acid (1.5 mL) was added to the reaction mixture while boiling Then the mixture
was cooled, and the resulting solid was collected and recrystallized from the appropriate solvent gave 2 and 3, respectively
Method C: A mixture of 1-(5-bromobenzofuran-2-yl)-3-(dimethylamino)prop-2-en-1-one (4) (1.47 g,
5 mmol) and the appropriate cyanothioacetamide or 2- cyanoacetohydrazide (5 mmol) in a solution of ethanol containing catalytical amount of piperdine (20 mL) was refluxed for 4–5 h The resulting solid
was collected and recrystallized to give identical in all aspects (mp., mixed mp and spectra) with 2 and
3, respectively
6-(5-Bromobenzofuran-2-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (2) Deep red crystals Yield:
65%, melting point: 172–174 °C (acetic acid) IR (KBr, cm−1): 3380 (NH), 3082 (CH), 2218 (CN), 1635 (C=N), 1570 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 6.97 (s, 1H, furan H-3), 7.28–7.66 (m, 4H,
ArH’s), 7.89–7.61 (d, 1H, J = 8.0 Hz, ArH’s), 14.42 (s, br., 1H, NH); 13C-NMR (400 MHz, DMSO-d6):
Trang 6δ = 101.5 (C18), 102.9 (C9), 114.1 (C1), 115.9 (C14), 116.5 (C16), 117.4 (C5), 122.3 (C2), 129.3 (C13),
129.5 (C15), 144.2 (C6), 148.7 (C8), 154.6 (C11), 159.1 (C8), 182.1 (C4); (CMS, m/z, (%); Calcd for
C14H7BrN2OS (331.19) C, 50.77; H, 2.13; Br, 24.13; N, 8.46; S, 9.68 Found: C, 50.66; H, 2.18; Br, 24.07; N, 8.41; S, 9.75
l-Amino-6-(5-bromo-benzofuran-2-yl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (3) Yellow crystals
Yield: 62%, melting point: > 300 °C (acetic acid) IR (KBr, cm−1): 3380,3260 (NH2), 3082 (CH), 2218 (CN), 1635 (C=N), 1570(C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 6.12 (s, br., 2H, NH2), 7.01 (s, 1H, benzofuran H-3), 7.32–8.17 (m, 5H, ArH’s); 13C-NMR (400 MHz, DMSO-d6): δ = 102.5 (C2), 104.7 (C9), 109.8 (C19), 114.1 (C16), 115.5 (C1), 116.5 (C14), 124.3 (C2), 125.4 (C13), 129.3 (C10), 129.57 (C1), 144.8 (C8), 152.1 (C6), 154.0 (C11), 164.4 (C4); Calcd for C1 4H8BrN3O2 (330.14) C, 50.93; H, 2.44; Br, 24.20; N, 12.73 Found: C, 50.88; H, 2.51; Br, 24.11; N, 12.65%
3.2 General Procedure for the Synthesis of
6-(5-bromobenzofuran-2-yl)-2-((2-oxopropyl)thio)-nicotinonitrile (5a), 6-(5-bromobenzofuran-2-yl)-2-(2-oxo-2-phenyl-ethylsulfanyl)-6-(5-bromobenzofuran-2-yl)-2-((2-oxopropyl)thio)-nicotinonitrile (5b) and 6-(5-bromobenzofuran-2-yl)-2-(methylthio)nicotinonitrile (5c)
Grinding Method: Equimolar amounts of 2 (1.66 g, 5 mmol) and potassium hydroxide (0.28 g, 5 mmol)
was ground with a pestle in an open mortar followed by the appropriate chloroacetone, ω-bromoacetophenone, or iodomethane (5 mmol) at room temperature for 2–3 min until the mixture turned into a melt The initial syrupy reaction mixture solidified within 3–5 min Grinding was continued for 5–10 min while the reaction was monitored by TLC The solid was washed with water and
recrystallized from N,N-dimethylformamide afforded the corresponding 5a–c, respectively
Traditional Method: A mixture of 6-(5-bromobenzofuran-2-yl)-2-mercaptonicotinonitrile (2) (1.66 g,
5 mmol) and potassium hydroxide (0.56 g, 5 mmol) in N,N-dimethylformamide (20 mL) was stirred for
2 h The appropriate chloroacetone, ω-bromoacetophenone or iodomethane (5 mmol) was added to the above mixture Then, the reaction was stirred for 2 h The resulting solid was formed after dilution of
water was collected and recrystallized from the proper solvent gave pyridine derivatives 5a–c, respectively
6-(5-Bromobenzofuran-2-yl)-2-((2-oxopropyl)thio)nicotinonitrile (5a) Brown crystals Yield: 84%,
melting point: 264–266 °C (dioxane) IR (KBr, cm−1): 3082 (CH), 2233 (CN), 1700 (CO), 1605 (C=N),
1570 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.39 (s, 3H, CH3), 4.38 (s, 2H, CH2), 7.23–7.97 (m, 6H, ArH’s); 13C-NMR (400 MHz, DMSO-d6): δ = 19.3 (C 12), 39.8 (C9), 102.8 (C13), 103.1 (C5), 114.1 (C20), 116.2 (C22), 116.5 (C18), 119.1 (C1), 125.3 (17), 129.3 (C14), 129.5 (C19), 136.1 (C6), 150.2 (C2), 154.0 (C15), 159.2 (C4), 159.6 (C8), 201.8 (C1); Calcd for C17H11BrN2O2S (387.25) C, 52.73; H, 2.86; Br, 20.63; N, 7.23; S, 8.28 Found: C, 52.67; H, 2.91; Br, 20.52; N, 7.15; S, 8.10%
6-(5-Bromobenzofuran-2-yl)-2-((2-oxo-2-phenylethyl)thio)nicotinonitrile (5b) Deep red crystals Yield:
80%, melting point: 184–186 °C (acetic acid) IR (KBr, cm−1): 3058 (CH), 2221 (CN), 1697 (CO), 1655 (C=N), 1527 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 4.58 (s, 2H, CH2), 7.23–8.00 (m, 11H, ArH’s);
13C-NMR (400 MHz, DMSO-d6): 37.1 (C18), 102.5 (C8), 103.1 (C5), 114.1 (C15), 116.2 (C19), 116.6 (C13), 119.0 (C1), 125.3 (C12), 128.5 (C24 & C28), 128.7 (C25 & C27), 129.3 (C9), 129.5 (C14), 133.1 (C26), 123.3 (C23), 136.0 (C6), 150.5 (C2), 154.0 (C10), 159.2 (C4), 159.6 (C7), 193.8 (C21), Calcd
Trang 7For C22H13BrN2O2S (449.32) C, 58.81; H, 2.92; Br, 17.78; N, 6.23; S, 7.14 Found: C, 58.92; H, 2.87;
Br, 17.84; N, 6.31; S, 7.00%
6-(5-Bromobenzofuran-2-yl)-2-(methylthio)pyridine-3-carbonitrile (5c) Brown crystals Yield: 73%,
melting point: 228–230 °C (dioxane) IR (KBr, cm−1): 3008 (CH), 2118 (CN), 1642 (C=O), 1566 (C=C);
1H-NMR (400 MHz, DMSO-d6): δ = 2.65 (s, 2H, CH2), 7.21–7.89 (m, 6H, ArH’s); 13C-NMR (400 MHz,
DMSO-d6): δ = 13.3 (C18), 102.1 (C8), 104.7 (C5), 114.1 (C15), 114.6 (C13), 116.5 (C13), 118.7 (C1), 125.3 (C12), 129.3 (C9), 129.5 (C14), 135.6 (C6), 150.1 (C2), 154.0 (C10), 159.6 (C7), 161.2 (C4); Calcd for C15H9BrN2OS (345.21) C, 52.19; H, 2.63; Br, 23.15; N, 8.11; S, 9.29 Found: C, 52.00; H, 2.57; Br, 23.08; N, 8.00; 8,9.35%
3.3 General Procedure for the Synthesis of
1-(3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridin-2-yl)ethan-1-one (6a), (3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridin-2-yl)(phenyl)methanone (6b), 3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridine-2-carbonitrile (6c) and ethyl 3-Amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridine-2-carboxylate (6d)
Method A: A mixture of 2 (1.66 g, 5 mmol) and potassium hydroxide (0.28 g, 5 mmol) in
N,Ndimethylformamide (10 mL) was stirred for 2 h at room temperature The appropriate of
chloroacetone, ω-bromoacetophenone, chloroacetonitrile or ethyl chloroacetate (10 mmol) was refluxed while stirring for 2 h The resulting solid formed after cooling and dilution with water was collected and
crystallized from N, N-dimethylformamide afforded 6a–d, respectively
Method B: A mixture of the appropriate 5a or 5b (5 mmol) in ethanol (15 mL) and piperidine (5 drops)
was heated under refluxed for 2 h The solid formed was collected and recrystallized gave products
identical in all aspects (mp., mixed mp and spectra) with 6a and 6b which were obtained from method A
1-(3-Amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridin-2-yl)ethanone (6a) Brown crystals
Yield: 84%, melting point: 279–281 °C (dioxane) IR (KBr, cm−1): 3274, 3174 (NH2), 3074 (CH), 1670 (CO), 1604 (C=N), 1570 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.36 (s, 2H, CH3), 6.90 (s, br., 2H, NH2), 7.52–8.70 (m, 6H, ArH’s); 13C-NMR (400 MHz, DMSO-d6): δ = 28.5 (C23), 102.8 (C13), 114.1 (C20), 116.5 (C18), 118.3 (C1), 122.3 (C5), 123.8 (C9), 125.3 (C17), 126.5 (C6), 129.3 (C14), 129.5 (C19), 136.0 (C10), 149.5 (C2), 153.8 (C15), 159.4 (C7), 160.0 (C4), 193.2 (C12) Calcd for
C17H11BrN2O2S (387.25) C, 52.73; H, 2.86; Br, 20.63; N, 7.23; S, 8.28 Found: C, 52.67; H, 2.78; Br, 20.58; N, 7.11; S, 8.348%
[3-Amino-6-(5-bromobenzofuran-2-yl)-thieno[2,3-b]pyridin-2-yl]-phenyl-methanone (6b) Brown crystals
Yield: 84%, melting point: 260–262 °C (dioxane) IR (KBr, cm−1): 3425, 3294, 3132 (NH2), 3070 (CH),
1672 (CO), 1593 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 6.80 (s, br., 2H, NH2), 7.44–8.28 (m, 11H, ArH’s); Calcd for C22H13BrN2O2S (449.32) C, 58.81; H, 2.92; Br, 17.78; N, 6.23; S, 7.14 Found: C, 58.75; H, 3.01; Br, 17.84; N, 6.32; S, 7.00%
2-(3-Amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridin-2-yl)-2-carbonitrile (6c) Brown crystals
Yield: 90%, melting point: 280–282 °C (dioxane) IR (KBr, cm−1): 3425, 3348, 3247 (NH2), 3070 (CH),
2194 (CN), 1658 (C=N), 1569 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 7.39–8.62 (m, 8H, ArH’s
Trang 8and NH2); Calcd for C16H8BrN3OS (370.22) C, 51.91; H, 2.18; Br, 21.58; N, 11.35; S, 8.66 Found: C, 52.01; H, 2.22; Br, 21.51; N, 11.39; 8,8.59%
Ethyl 3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridine-2-carboxylate (6d) Yellow crystals
Yield: 87%, melting point: 290–292 °C (dioxan) IR (KBr, cm−1): 3293, 3197 (NH2), 2979 (CH), 1670 (CO), 1611 (C=N), 1556 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 1.30 (t, 3H, J = 7.5 Hz, CH2CH3),
4.27 (q, 2H, J = 7.5 Hz, CH2CH3), 7.34–8.64 (m, 8H, ArH’s and NH2); 13C-NMR (400 MHz, DMSO-d6):
δ = 8.3 (C24), 33.7 (C23), 102.7 (C13), 114.2 (C20), 116.5 ( C18), 118.6 (C1), 121.5 (C5), 125.0 (C17), 126.3 (C9), 126.7 (C6), 129.3 (C14), 129.6 (C19), 135.4 (C10), 149.5 (C2), 154.0 (C15), 159.6 (C7), 160.0 (C4), 198.5 (C12) Calcd for C18H13BrN2O3S (417.28) C, 51.81; H, 3.14; Br, 19.15; N, 6.71; S, 7.68 Found: C, 51.92; H, 3.24; Br, 19.00; N, 6.61; 8,7.72%
3.4 Synthesis of 7-(5-bromobenzofuran-2-yl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-one (7), 7-(5-bromobenzofuran-2-yl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine (8) and ethyl
(E)-N-(6-(5-Bromobenzofuran-2-yl)-2-cyanothieno[2,3-b]pyridin-3-yl)formimidate (9)
7-(5-bromobenzofuran-2-yl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-one (7) A mixture of 6c
(1.85 g, 5 mmol) and formic acid (7 mL, 99%) in N,N,-dimethylformamide (5 mL) was boiled under
reflux for 7 h The reaction mixture was poured onto ice (30 g) The solid so formed was collected and
recrystallized from DMF gave 7 as brown crystals Yield: 72%, melting point: > 300 °C (DMF) IR
(KBr, cm−1): 3320 (NH), 3001 (CH), 1666 (CO), 1569 (C=C); 1H-NMR (400 MHz, DMSO-d6):
δ = 7.01–8.21 (m, 7H, ArH’s), 12.85 (s, br., 1H, NH); MS, m/z, (%): 399 (M+1, 29%), 398 (M+, 100%),
397 (M−1,12%), 371 (17%), 370 (67%), 200 (7%), 199 (7%), 105 (10%), 77 (27%); Calcd for
C17H8BrN3O2S (398.23) C, 51.27; H, 2.02; Br, 20.06; N, 10.55; S, 8.05 Found: C, 51.15; H, 1.95; Br, 20.00; N, 10.42; S, 7.87%
7-(5-bromobenzofuran-2-yl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine (8) Method A: A mixture
of 6c (1.85 g, 5 mmol) and formamide (5 mL, 99%) in N,N,-dimethylformarnide (5 mL) was boiled
under reflux for 7 h The reaction mixture was poured onto ice (30 g) recrystallized from DMF to give
8 as brown crystals Yield: 78%, melting point: > 300 °C The solid so formed was collected and (DMF)
IR (KBr, cm−1): 3320, 3151 (NH2), 3001 (CH), 1648 (C=N), 1573 (C=C); 1H-NMR (400 MHz, DMSO-d6):
δ = 6.88 (s, br., 2H, NH2), 7.31–8.11 (m, 7H, ArH’s); MS, m/z (%): 399 (M+2, 29%), 398 (M+1, 100%),
397 (M+,12%), 371 (17%), 370 (67%), 200 (7%), 199 (7%), 105 (10%), 77 (27%); Calcd for
C17H9BrN4OS (397.25) C, 51.40; H, 2.28; Br, 20.11; N, 14.10; S, 8.07 Found: C, 51.31; H, 2.32; Br,
20.00; N, 14.23; S, 7.88% Method B: A mixture of ethyl N-[6-(5-bromo-benzofuran-2-yl)-2-cyano-thieno[2,3-b]pyridin-3-yl]-formimidoate (9) (0.5 g) and formamide (0.5 mL) in N,N,-dimethylformamide
(5 mL) was boiled for 2 h The solid so formed was collected and recrystallized from DMF gave a product
identical in all aspects (mp., mixed mp and spectra) with product 8
Ethyl N-[6-(5-bromobenzofuran-2-yl)-2-cyano-thieno[2,3-b]pyridin-3-yl]-formimidoate (9) A mixture
of 2d (1.85 g, 5 mmol) and triethyl ortho-formate (1.48 g, 10 mmol) in acetic anhydride (20 mL) was
heated under reflux for 6 h The reaction mixture was poured onto ice (30 g) The resulting solid was
collected and recrystallized from dioxane gave 9 as brown crystals Yield: 71%, melting point: 250–252 °C
(dioxane) IR (KBr, cm−1): 3070 (CH), 2194 (CN), 1648 (C=N), 1573 (OC); 1H-NMR (400 MHz,
Trang 9DMSO-d6): δ = 1.37 (t, 3H, J = 8.0 Hz, CH2CH3), 4.32 (q, 2H, J = 8.0 Hz, CH2CH3), 7.31–8.22 (m, 7H, ArH’s and CH=); 13C-NMR (400 MHz, DMSO-d6): δ = 15.3 (C25), 62.6 (C24), 101.7 (C9), 102.2 (C13), 113.7 (C12), 113.0 (C12), 114.2 (C20), 116.6 (C18), 118.4 (C1), 125.3 (C16), 125.5 (C5), 127.6 (C6), 129.3 (C13), 129.6 (C18), 133.2 (C10), 149.1 (C2), 153.8 (C14), 157.1 (C21), 159.7 (C7), 161.1 (C4) Calcd for C19H12BrN3O2S (426.29) C, 53.53; H, 2.84; N, 9.86; S, 7.52 Found: C, 53.39; H, 2.75; Br, 18.68; N, 10.00; S, 7.41%
3.5 Pyridine Derivatives 10–14
l-(5-Bromobenzofuran-2-yl)-3-(dimethylamino)prop-2-en-l-one (3) (1.86 g, 5 mmol), the appropriate
acetylacetone, ethyl acetoacetate, ethyl cyanoacetate, malononitrile, benzoylacetonitrile, (5 mmol) and ammonium acetate (0.38 g, 5 mmol), was heated in acetic acid (10 mL) under reflux for 3 h on cooling, the separated solid was filtered, washed with water and crystallized from the proper solvent afforded
10–14, respectively
l-(6-(5-Bromobenzofuran-2-yl)-2-methylpyridin-3-yl)ethanone (10) Beige crystals, Yield: 84%, melting
point: 160–162 °C (acetic acid) IR (KBr, cm−1): 3001 (CH), 1710 (CO), 1648 (C=N), 1573 (C=C); 1H-NMR
(400 MHz, DMSO-d6): δ = 2.51 (s, 3H, CH3), 2.57 (s, 3H, CH3), 7.31–7.89 (m, 6H, ArH’s); 13C-NMR (400 MHz, DMSO-d6): δ = 24.6 (C7), 28.5 (C9), 102.2 (C12), 114.1 (C19), 116.7 (C16), 118.8 (C1), 124.9 (C16), 129.0 (C13), 129.5 (C18), 131.2 (C6), 133.1 (C5), 152.2 (C1), 153.7 (C14), 158.0 (C4), 160.2
(C11), 201.1 (C8) MS, m/z, (%): 331 (M+1, 78%), 329 (M−1, 83%), 316 (100%), 314 (94%), 288 (16%),
286 (16%), 207 (48%), 204 (48%), 152 (18%), 150 (13%), 89 (25%), 77 (16%), 63 (36%); Calcd for
C16H12BrNO2 (330.18) C, 58.20; H, 3.66; Br, 24.20; N, 4.24 Found: C, 58.12; H, 3.58; Br, 24.00; N, 4.18%
Ethyl 6-(5-bromobenzofuran-2-yl)-2-methylpyridine-3-carboxylate (11) Yellow crystals, Yield: 85%,
melting point: 176–178 °C (dioxane) IR (KBr, cm−1): 3058 (CH), 1708 (CO), 1639 (C=N), 1585 (C=C);
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (t, 3H, J = 8.0 Hz, CH2CH3), 2.62 (s, 3H, CH3), 4.22 (q, 2H,
J = 8.0 Hz, CH2CH3), 7.28–7.98 (m, 6H, ArH’s); MS, m/z, (%)): 361 (M+1, 64%), 359 (M−1, 100%),
317 (46%), 315 (63%), 259 (45%), 247 (63%), 89 (45%), 97 (45%), 62 (64%); 13C-NMR (400 MHz, DMSO-d6): δ = 14.2 (C22), 24.3 (C7), 61.8 (C22), 102.8 (C12), 114.0 (C19), 116.5 (C17), 120.1 (C1), 124.8 (C16), 125.0 (C5), 129.2 (C13), 129.7 (C18), 130.2 (C6), 148.8 (C2), 153.9 (C14), 157.0 (C4), 160.0 (C11), 166.8 (C8) Calcd for C17H14BrNO3 (360.2) C, 56.69; H, 3.92; Br, 22.18; N, 3.89 Found:
C, 56.58; H, 4.11; Br, 22.07; N, 3.96%
Ethyl 2-Amino-6-(5-bromobenzofuran-2-yl)pyridine-3-carboxylate (12) Yellow crystals, Yield: 90%,
melting point: 220–222 °C (dioxane) IR (KBr, cm−1): 3078 (CH), 1701 (CO), 1643 (C=N), 1550 (C=C);
1H-NMR (400 MHz, DMSO-d6): δ = 1.35 (t, 3H, J = 8.0 Hz, CH2CH3), 4.23 (q, 2H, J = 8.0 Hz, CH2CH3), 7.30–8.10 (m, 8H, NH2 and ArH’s); MS, m/z, (%): 362 (M+1, 53%), 360 (M−1, 50%), 290 (53%), 149
(53%), 90 (100%), 89 (53%), 81 (70%), 75 (47%); Calcd for C16H13BrN2O3 (361.19) C, 53.21; H, 3.63;
Br, 22.12; N, 7.76 Found: C, 53.27; H, 3.69; Br, 22.00; N, 7.68%
2-Amino-6-(5-bromobenzofuran-2-yl)pyridine-3-carbonitrile (13) Brown crystals, Yield: 80%, melting
point: 270–272 °C (dioxane) IR (KBr, cm−1): 3344, 3105 (NH2), 3078 (CH), 2218 (CN), 1653 (C=N),
1585 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 6.21 (s, br., 2H, NH2), 7.30–8.22 (m, 6H, ArH’s);
Trang 10MS, m/z, (%): 315 (M+1, 94%), 313 (M−1, 100%), 289 (11%), 287 (12%), 164 (11%), 129 (11%), 127
(16%), 75 (25%); Calcd for C14H8BrN3O (314.14) C, 53.53; H, 2.57; Br, 25.44; N, 13.38 Found: C, 53.48; H, 2.61; Br, 25.33; N, 13.29%
(2-Amino-6-(5-bromobenzofuran-2-yl)pyridin-3yl)(phenyl)methanone (14) Brown crystals, Yield:
90%, melting point: 240–242 °C (acetic acid) IR (KBr, cm−1): 3344, 3105 (NH2), 3078 (CH), 1680 (CO), 1624 (C=N), 1577 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 7.30–7.79 (m, 11H, ArH’s), 10.21 (s, br., 2H, NH2); MS, m/z, (%): 394 (M+1, 77%), 393 (M+, 54%), 392 (17%), 290 (33), 288 (35%), 224 (68%), 222 (67%), 168 (17%), 166 (52%), 146 (15%), 144 (17%), 109 (56%), 88 (97%), 75 (31%); Calcd for C20H13BrN2O2 (393.23) C, 61.09; H, 3.33; Br, 20.32; N, 7.12 Found: C, 61.15; H, 3.42; Br, 20.12;
N, 7.00%
6-(5-Bromobenzofuran-2-yl)-2-methylpyridine-3-carbohydrazide (15) A mixture of 12 (1.85 g, 5 mmol)
and hydrazine hydrate (1 g, 20 mmol) in ethanol (20 mL) was heated under refluxed for 3 h The resulting solid was collected and recrystallized from acetic acid gave a beige crystals Yield: 96%, melting point: 250–252 °C IR (KBr, cm−1): 3388, 3337, 3217 (NH, NH2), 3062 (CH), 2920, 2851 (CH), 1680 (CO),
1640 (C=N), 1589 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.62 (s, 3H, CH3), 6.24 (s, br., 3H, NH and NH2), 7.23–7.89 (m, 6H, ArH’s); MS, m/z, (%): 347 (M+1, 15%), 345 (M−1, 13%), 315 (79%), 314
(100%), 313 (86%), 207 (43%), 205 (40%), 152 (20%), 151 (23%), 150 (0%), 103 (18%), 77 (25%), 63 (43%); Calcd for C15H12BrN3O2 (346.18) C, 52.04; H, 3.49; Br, 23.08; N, 12.14 Found: C, 52.04; H, 3.49; Br, 23.08; N, 12.14%
3.6 1-(6-(5-Bromobenzofuran-2-yl)-2-methylnicotinoyl)-3-methyl-1H-pyrazol-5(4H)-one (16a) and (6-(5-Bromobenzofuran-2-yl)-2-methylpyridin-3-yl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (16b)
A mixture of 6-(5-bromobenzofuran-2-yl)-2-methylpyridine-3-carbohydrazide (15) (1.73 g, 5 mmol),
ethyl acetoacetate or acetylacetone in ethanol (20 mL) and acetic acid (5 drops) was heated under reflux
for 3 h on cooling, the separated yellow solid was filtered, washed with water and crystallized gave 16a and 16b, respectively
1-(6-(5-Bromobenzofuran-2-yl)-2-methylnicotinoyl)-3-methyl-1H-pyrazol-5(4H)-one (16a) Yellow
crystals, Yield: 87%, melting point: 260–262 °C (DMF) IR (KBr, cm−1): 2920 (CH), 1687 (CO), 1639 (C=N), 1589 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.10 (s, 3H, CH3), 2.64 (s, 3H, CH3), 3.42 (q, 1H, CH2), 3.62 (q, 1H, CH2), 7.30–7.95 (m, 6H, ArH’s); MS, m/z, (%): 413 (M+1, 19%), 411 (M−1,
18%), 98 (48%), 91 (22%), 88 (44%), 86 (30%), 80 (85%), 64 (44%); Calcd for C19H14BrN3O3 (412.24)
C, 55.36; H, 3.42; Br, 19.38; N, 10.19 Found: C, 55.41; H, 3.38; Br, 19.28; N, 10.00%
(6-(5-Bromobenzofuran-2-yl)-2-methylpyridin-3-yl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (16b)
Yellow crystals, Yield: 91%, melting point: 272–274 °C (dioxan) IR (KBr, cm−1): 2977 (CH), 1681 (CO), 1585 (OC); 1H-NMR (400 MHz, DMSO-d6): δ = 2.30 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.66 (s, 3H, CH3), 5.78 (s, 1H, pyrazole H-4), 7.30–7.99 (m, 6H, ArH’s); MS, m/z, (%): 410 (M+, 100%), 331 (48%), 316 (5%), 314 (8%), 289 (10%), 206 (16%), 179 (49%), 167 (16%), 165 (11%), 139 (11%), 137